Lemierre's Syndrome: A Case of a Large Inammatory Neck Mass with Internal Jugular Vein Thrombosis and Literature Review of Its Surgical Intervention

Background: Lemierre's syndrome is a fatal and rare disease that is typically characterized by oropharyngeal infection and internal jugular vein thrombosis. Timely application of appropriate antibiotics is the standard treatment. However, when conservative medical treatment fails to have effect, surgical intervention may be the only effective option for controlling the source of infection. Case presentation: The authors report a case of Lemierre's syndrome with a large inammatory neck mass involving left internal jugular vein thrombosis that was cured by surgical treatment. In addition, a literature review was carried out through PubMed using the terms “Lemierre’s syndrome/disease and review, meta-analysis or retrospective study” and “Lemierre’s syndrome/disease and internal jugular vein”. This search yielded 6 articles that recorded the surgical rate in detail. Conclusion: The purpose of this review was to summarize the conditions under which surgical treatment are conducted. Additionally, this is the rst report of such a large inammatory neck mass that was completely cured by surgical resection and internal jugular vein ligation. The authors further offer several conclusions regarding surgical intervention in Lemierre’s syndrome.

Conclusion: The purpose of this review was to summarize the conditions under which surgical treatment are conducted. Additionally, this is the rst report of such a large in ammatory neck mass that was completely cured by surgical resection and internal jugular vein ligation. The authors further offer several conclusions regarding surgical intervention in Lemierre's syndrome.

Background
Internal jugular vein (IJV) thrombosis is a relatively rare and urgent disease. In a retrospective study, the number of such cases occurring from 2001 to 2008 was 2.5 times that occurring from 1991 to 2000 and 20 times that occurring from 1980 to 1990 [1]. The reasons behind the increasing incidence of IJV thrombosis include the advancement of antibiotic resistance, widespread use of hemodialysis, general application of central venous catheters, expansion of assisted reproductive technology, and increasing incidence of cancer [2]. In a nine-year retrospective study of 1,948 patients with deep vein thrombosis, only 29 patients developed IJV thrombosis, of whom 23 had IJV thrombosis secondary to another condition, such as a malignancy (e.g., Trousseau syndrome), central venous catheter implantation, or ovarian hyperstimulation syndrome (OHSS) [3]. In addition, bilateral internal jugular vein thrombosis is an important indicator of malignant tumors. In a 5-year retrospective study of 41 patients with IJV thrombosis in Germany, paraneoplastic thrombosis accounted for 54% of cases; of these cases, otolaryngology head and neck diseases accounted for 68%. The other patients mostly had in ammatory diseases [4].
In the ear, nose and throat (ENT) eld, IJV thrombosis is commonly associated with Lemierre's syndrome (LS), which is a complication of infectious diseases, such as otitis media and oropharyngeal abscess or infection. LS is commonly de ned by the following diagnostic criteria: 1) oropharyngeal infection; 2) internal jugular vein thrombophlebitis or thrombosis; 3) septic emboli at a remote site, more frequently the lungs; and 4) isolation of Fusobacterium nucleatum on blood culture [5]. LS is usually accompanied by septic emboli in the lungs or other organs [6]. Under some rare conditions, LS can also be triggered by tooth extraction [7]. Pulmonary embolism, with an incidence of approximately 10%, and postthrombotic syndromes, such as limb pain, heaviness, venous dilatation, edema, pigmentation, nutritional skin changes, and venous ulcers, are complications of IJV thrombosis [4]. Therefore, ENT doctors should give enough attention to patients with IJV thrombosis to avoid the disastrous results caused by pulmonary or cerebral thrombosis.
To the best of our knowledge, this is the rst case of such a large infectious neck mass with internal jugular vein thrombosis that was completely cured by surgical intervention.

Case Presentation
A 67-year-old male developed pain in the left neck 14 days prior after eating mud sh. He was healthy and denied a history of infectious diseases, chronic diseases, surgical trauma, blood transfusion, allergies or contact with poisonous substances. Physical examination on admission revealed the following: fever, chills, fatigue, mild dysuria, diffusive swelling pain of the neck on the left side, and high skin temperature. His left neck was tender and edematous with cellulitis. The mass was scleroid with a lique ed center. Other parameters were as follows: white blood cell (WBC) count, 12.2*10 9 /L; neutrophil count, 11.76*10 9 /L; platelet (PLT) count, 51*10 9 /L; C-reactive protein (CRP) level, 146 mg/L; procalcitonin (PCT), 156.99 ng/ml; temperature, 39.5°C; respiratory rate, 24/minute; pulse, 118/minute; and blood pressure (BP), 109/61 mmHg. This patient stated that he had been to many hospitals and that antibiotics like cephalosporin slightly alleviated his neck pain at rst. However, the effect was temporary and no longer present after he transferred to Shanghai. Three days before he presented to our hospital, he felt extreme swelling and pain again in the area of his neck mass (  (Fig. 2). Video laryngoscopy excluded the possibility of pyriform sinus stula or any foreign body. Pus obtained from the mass showed many neutrophils and large amounts of necrotic tissue. No microbes could be isolated from the samples (blood and pus). The infectious disease and nephrology departments were consulted. Fourteen days of combination antibiotic treatment and regular insulin treatment returned the patient's temperature, routine blood markers, CRP and PCT levels and coagulation function to normal. However, the neck mass remained. Therefore, the surgery department was consulted.
The patient was taken to the operating room. The neck mass adhered tightly to the surrounding tissue, and the involved segment of the left internal jugular vein was exposed by sharp dissection (Fig. 3). The proximal part of the mass needed to be ligated rst to avoid small thrombus detachment. There was a large amount of in ammation and brosis present in the involved area. The involved segment of the internal jugular vein and the whole neck mass were completely resected, and the distal part of the internal jugular vein was fully ligated (Fig. 4). The pathological examination showed hemorrhagic necrosis with the proliferation of brous and granulation tissue and the accumulation of foam-like cells and multinuclear giant cells (Fig. 5).

Literature review
It is rare that patients with Lemierre's syndrome require surgical intervention when antibiotics and anticoagulant therapies fail. This is the rst study to summarize cases of LS requiring surgical treatment (not including abscess drainage). First, we decided to collect previous reviews and meta-analyses to obtain good knowledge of the rate of surgery in LS. Search strategy and selection criteria: A search of the literature in MEDLINE was performed through PubMed to identify relevant English language articles. The following search terms were used: "Lemierre's syndrome/disease and review, meta-analysis or retrospective study" and "Lemierre's syndrome/disease and internal jugular vein". The references of the retrieved articles were also reviewed to identify additional sources. Through reading the abstract and the full text, we found a total of 6 reviews and meta-analyses ( Table 1) that included detailed descriptions of patients who underwent surgery (not including abscess drainage). In a retrospective review from 1998-2010 at a local tertiary referral hospital, 17 of the 23 patients underwent surgical treatment of the primary infection site [8]. In a ve-year systematic review, surgical procedures, such as tooth extraction, craniotomy and ligation of the occluded vein, were performed in 5 patients to prevent further septic emboli [9]. A retrospective study from June 2000 to May 2016 showed that IJV ligation was performed in only one of ve LS cases at the Children's Hospital of Alabama [10]. In an 8-year Swedish nationwide retrospective study, three patients with peritonsillitis were surgically treated by tonsillectomy [11]. In the latest meta-analysis of 394 patients in 2020, only 10 patients underwent IJV ligation/excision, only 1 patient underwent ligation/excision of the thrombosed external carotid artery, 3 underwent endoscopic sinus surgery and 11 underwent mastoidectomy [12]. In the latest systematic review, which included the most LS cases reported, surgical procedures were performed in 101 patients, and 31 patients underwent IJV ligation/embolectomy [13]. patients, the most common rst clinical presentation was a sore throat (33%), followed by a neck mass (23%) and neck pain (20%) [1]. In the current case, the patient presented with fever and neck pain at rst, followed by a neck mass. The use of antibiotics before he was transferred to our hospital was ineffective.
The white blood cell count, PCT level, and ESR were elevated, and blood appeared in his urine. We adjusted the treatment to the combined application of broad-spectrum antibiotics, including imipenem and teicoplanin, for another 2 weeks. The patient's body temperature returned to normal and laboratory testing showed that the patient's infectious condition had been controlled, but the neck mass and internal jugular vein thrombosis persisted and required surgical treatment.
Fusobacterium necrophorum is the main pathogen of Lemierre's syndrome [1]. However, in this case, the culture of both blood and uid obtained from the mass was negative for bacteria, which might be because the patient had been treated with antibiotics for nearly 2 weeks before coming to our hospital.
This also suggests that it is particularly important for doctors to culture blood or uid from the mass before the use of antibiotics in these patients.
The diagnosis of internal jugular vein thrombosis in Lemierre's syndrome relies on imaging examination. Ultrasound is the rst choice for the diagnosis of LS, and computed tomography (CT) and magnetic resonance imaging (MRI) are currently implemented in general practice when necessary. Albertyn et al.
rst summarized the classic imaging features of internal jugular vein thrombosis. Ultrasonography shows the vein to be distended and nonpulsatile, with internal echoes. CT shows swelling of the adjacent soft tissues, distension of the vein with wall enhancement, and low-attenuation intraluminal lling defects. However, ultrasound has limitations and cannot display the anatomy behind the clavicle or mandible [16]. In this case, we found that although US can clearly show internal jugular vein thrombosis, knowing its boundaries and connection with the tumor still depends on CT or MRI, especially when there is an urgent need for surgery. A full assessment by preoperative imaging is of great importance. This is also consistent with the views of Charles et al [17].
Priority treatment for LS includes antibiotic therapy and drainage of the infected site. Rarely, other surgical procedures, such as ligation of the occluded vein, craniotomy and tooth extraction, are performed. Antithrombotic therapy, including novel oral anticoagulants (DOACs), is also recommended depending on the individual's condition. However, it remains controversial whether anticoagulation or antithrombotics are effective in Lemierre's syndrome. Some scholars think that thrombosis is due to the infection process and can be resolved when the infection has been controlled [18]. In this case, we did not immediately apply anticoagulant or thrombolytic therapies considering that the APTT of this patient was signi cantly prolonged at the time he came to our hospital and the consumption of platelets was relatively high; emergency anticoagulant therapy may have increased his risk of bleeding. To date, there have been no su cient clinical studies and is no su cient evidence suggesting the necessity for anticoagulant therapy in Lemierre's syndrome [19]. Previous studies have also reported the occurrence of extensive suppurative thrombophlebitis of the bilateral IJV and superior vena cava in patients with Lemierre's syndrome despite the use of antibiotics and anticoagulant therapy; adjunctive catheter-directed thrombolysis and superior vena cava stenting were performed to help these patients completely recover [20]. Anticoagulation therapy has not been shown to reduce the complications of Lemierre's syndrome, such as sepsis [17]. Meanwhile, Johannesen et al. did not nd that anticoagulation therapy decreased the mortality rate or course of the disease or reduced the duration of antibiotic use [21].
However, anticoagulation therapy is recommended in patients with a poor clinical response despite antibiotic therapy and with a high risk of intracranial thrombosis or recurrent thrombophlebitis [22][23][24]. In this case, the cause of internal jugular vein thrombosis was largely infection, so surgical treatment was the best choice when antibiotics could not completely cure the infection and thrombosis. Through previous retrospective studies, systematic reviews and meta-analyses obtained by database searches, we summarized the following points regarding surgical intervention in Lemierre's syndrome: (1) When patients do not respond to conservative medical therapy and continue to show extensive septic thrombosis or uncontrolled severe sepsis, surgical treatments need to be considered.
(2) Abscess drainage is the most common and convenient surgical treatment for abscesses upon formation.
(3) Surgical treatment of the primary infection site is effective for controlling the spread of infection and sepsis.
(4) IJV ligation or excision is suitable for patients with persistent septic embolization after treatment with antibiotics and anticoagulants.
(5) IJV ligation or excision is also appropriate to avoid thrombus detachment when anticoagulation therapy or catheter-directed thrombolysis is ineffective.

Conclusion
Lemierre's syndrome is an extremely rare disease, but the fatality rate can reach 15%, even with escalating antibiotic therapy [20]. Therefore, early diagnosis is particularly important, and the timely application of appropriate antibiotics is the standard treatment. Surgical intervention may be the only effective option for controlling the source of infection or when conservative medical treatment fails. The studies involving human participants were reviewed and approved by Human Ethics Committee, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine. The patient provided their written informed consent for the use of his images and other clinical information in this study. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Consent for publication
Not applicable.
Availability of data and materials Not applicable.

Competing interest
There are no con icts of interest.

Funding
Not applicable.

Authors' contributions
Minglinag Xiang did the whole operation and checked review. Yilin Shen and Bin Ye have wrote article and made review. Chaofu Wang and Qian Da provided the pathological images.

Figure 1
Picture of the patient's neck showed a huge mass with tenderness.   The resected neck mass as well as left IJV was showed. Intraluminal thrombosis could be seen clearly when opening the internal jugular vein.